André Berndt Penteado, Geovani de Oliveira Ribeiro, Emerson Luiz Lima Araújo, Rodrigo Bentes Kato, Caio Cesar de Melo Freire, Joselio Maria Galvão de Araújo, Gabriel da Luz Wallau, Richard Steiner Salvato, Ronaldo de Jesus, Geraldine Goés Bosco, Helena Ferreira Franz, Pedro Eduardo Almeida da Silva, Elcio de Souza Leal, Gustavo Henrique Goulart Trossini, Daniel Ferreira de Lima Neto
The Red Queen Hypothesis (RQH), derived from Lewis Carroll's "Through the Looking-Glass", postulates that organisms must continually adapt in response to each other to maintain relative fitness. Within the context of host-pathogen interactions, the RQH implies an evolutionary arms race, wherein viruses evolve to exploit hosts and hosts evolve to resist viral invasion. This study delves into the dynamics of the RQH in the context of virus-cell interactions, specifically focusing on virus receptors and cell receptors...
April 18, 2024: Journal of Molecular Biology
Chih-Hsuan Lee, Jing-Ee Saw, Eric H-L Chen, Chun-Hsiung Wang, Takayuki Uchihashi, Rita P-Y Chen
Prions, the misfolding form of prion proteins, are contagious proteinaceous macromolecules. Recent studies have shown that infectious prion fibrils formed in the brain and non-infectious fibrils formed from recombinant prion protein in a partially denaturing condition have distinct structures. The amyloid core of the in vitro-prepared non-infectious fibrils starts at about residue 160, while that of infectious prion fibrils formed in the brain involves a longer sequence (residues ∼90-230) of structural conversion...
April 17, 2024: Journal of Molecular Biology
Kenji Fukui, Yuki Fujii, Takato Yano
DNA mismatch repair endonuclease MutL is a member of GHKL ATPase superfamily. Mutations of MutL homologs are causative of a hereditary cancer, Lynch syndrome. We characterized MutL homologs from human and a hyperthermophile, Aquifex aeolicus, (aqMutL) to reveal the catalytic mechanism for the ATPase activity. Although involvement of a basic residue had not been conceived in the catalytic mechanism, analysis of the pH dependence of the aqMutL ATPase activity revealed that the reaction is catalyzed by a residue with an alkaline pKa ...
April 17, 2024: Journal of Molecular Biology
Javier Lizarrondo, Florian Wilfling
Proteins are known to perform an astonishing array of functions thanks to their ability to cooperate and modulate each other's properties. Inside cells, proteins can assemble into large multi-subunit complexes to carry out complex cellular functions. The correct assembly and maintenance of the functional state of macromolecular protein complexes is crucial for human health. Failure to do so leads to loss of function and potential accumulation of harmful materials, which is associated with a variety of human diseases such as neurodegeneration and cancer...
April 16, 2024: Journal of Molecular Biology
Andrea Vannini, Eva Pinatel, Paolo Emidio Costantini, Simone Pelliciari, Davide Roncarati, Simone Puccio, Gianluca De Bellis, Vincenzo Scarlato, Clelia Peano, Alberto Danielli
Iron homeostasis is a critical process for living organisms because this metal is an essential co-factor for fundamental biochemical activities, like energy production and detoxification, albeit its excess quickly leads to cell intoxication. The protein Fur (ferric uptake regulator) controls iron homeostasis in bacteria by switching from its apo- to holo-form as a function of the cytoplasmic level of ferrous ions, thereby modulating gene expression. The Helicobacter pylori HpFur protein has the rare ability to operate as a transcriptional commutator; apo- and holo-HpFur function as two different repressors with distinct DNA binding recognition properties for specific sets of target genes...
April 14, 2024: Journal of Molecular Biology
Reza Talandashti, Larissa van Ek, Charlotte Gehin, Dandan Xue, Mahmoud Moqadam, Anne-Claude Gavin, Nathalie Reuter
STARD4 regulates cholesterol homeostasis by transferring cholesterol between the plasma membrane and endoplasmic reticulum. The STARD4 structure features a helix-grip fold surrounding a large hydrophobic cavity holding the sterol. Its access is controlled by a gate formed by the Ω1 and Ω4 loops and the C-terminal α-helix. Little is known about the mechanisms by which STARD4 binds to membranes and extracts/releases cholesterol. All available structures of STARD4 are without a bound sterol and display the same closed conformation of the gate...
April 12, 2024: Journal of Molecular Biology
Verónica Pulido, Jose M Rodríguez-Peña, Graciela Alonso, Ana Belén Sanz, Javier Arroyo, Raúl García
Cellular mRNA levels, particularly under stress conditions, can be finely regulated by the coordinated action of transcription and degradation processes. Elements of the 5'-3' mRNA degradation pathway, functionally associated with the exonuclease Xrn1, can bind to nuclear chromatin and modulate gene transcription. Within this group are the so-called decapping activators, including Pat1, Dhh1, and Lsm1. In this work, we have investigated the role of Pat1 in the yeast adaptive transcriptional response to cell wall stress...
April 9, 2024: Journal of Molecular Biology
Hua-Chang Chen, Jing Wang, Robert J Coffey, James G Patton, Alissa M Weaver, Yu Shyr, Qi Liu
Extracellular vesicles and particles (EVPs) play a crucial role in mediating cell-to-cell communication by transporting various molecular cargos, with small non-coding RNAs (ncRNAs) holding particular significance. A thorough investigation into the abundance and sorting mechanisms of ncRNA within EVPs is imperative for advancing their clinical applications. We have developed EVPsort, which not only provides an extensive overview of ncRNA profiling in 3,162 samples across various biofluids, cell lines, and disease contexts but also seamlessly integrates 19 external databases and tools...
April 9, 2024: Journal of Molecular Biology
Pietro Ancona, Alessandro Trentini, Anna Terrazzan, Silvia Grassilli, Pauline Navals, Eric W J Gates, Valentina Rosta, Carlo Cervellati, Carlo M Bergamini, Angela Pignatelli, Jeffrey W Keillor, Cristian Taccioli, Nicoletta Bianchi
Transglutaminase 2 (TG2) performs many functions both under physiological and pathological conditions. In cancer, its expression is associated with aggressiveness, propensity to epithelial-mesenchymal transition, and metastasis. Since TG2 performs key functions both outside and inside the cell, using inhibitors with different membrane permeability we analyzed the changes in the transcriptome induced in two triple-negative cell lines (MDA-MB-436 and MDA-MB-231) with aggressive features. By characterizing pathways and gene networks, we were able to define the effects of TG2 inhibitors (AA9, membrane-permeable, and NCEG2, impermeable) in relation to the roles of the enzyme in the intra- and extracellular space within the context of breast cancer...
April 9, 2024: Journal of Molecular Biology
Jeremy W Schroeder, P Lydia Freddolino
A pervasive question in biological research studying gene regulation, chromatin structure, or genomics is where, and to what extent, does a signal of interest arise genome-wide? This question is addressed using a variety of methods relying on high-throughput sequencing data as their final output, including ChIP-seq for protein-DNA interactions [1], GapR-seq for measuring supercoiling [2], and HBD-seq or DRIP-seq for R-loop positioning [3,4]. Current computational methods to calculate genome-wide enrichment of the signal of interest usually do not properly handle the count-based nature of sequencing data, they often do not make use of the local correlation structure of sequencing data, and they do not apply any regularization of enrichment estimates...
April 5, 2024: Journal of Molecular Biology
Fan Bu, Xiaoxuan Wang, Mengke Li, Li Ma, Chuan Wang, Yangbo Hu, Zhengguo Cao, Bin Liu
Porphyromonas gingivalis, an anaerobic CFB (Cytophaga, Fusobacterium, and Bacteroides) group bacterium, is the keystone pathogen of periodontitis and has been implicated in various systemic diseases. Increased antibiotic resistance and lack of effective antibiotics necessitate a search for new intervention strategies. Here we report a 3.5 Å resolution cryo-EM structure of P. gingivalis RNA polymerase (RNAP). The structure displays new structural features in its ω subunit and multiple domains in β and β' subunits, which differ from their counterparts in other bacterial RNAPs...
April 5, 2024: Journal of Molecular Biology
Min Li, Renbin Yang, Xuemin Chen, Huaibin Wang, Rodolfo Ghirlando, Emilios K Dimitriadis, Robert Craigie
Retroviral DNA integration is mediated by nucleoprotein complexes (intasomes) in which a pair of viral DNA ends are bridged by a multimer of integrase (IN). Most of the high-resolution structures of HIV-1 intasomes are based on an HIV-1 IN with an Sso7d protein domain fused to the N-terminus. Sso7d-IN aggregates much less than wild-type IN and has been critical for structural studies of HIV-1 intasomes. Unexpectedly, these structures revealed that the common core architecture that mediates catalysis could be assembled in various ways, giving rise to both tetrameric and dodecameric intasomes, together with other less well-characterized species...
April 4, 2024: Journal of Molecular Biology
Andrea L Rocha, Victor Pai, Guy Perkins, Tina Chang, Jiao Ma, Qian Chu, Joan M Vaughan, Jolene K Diedrich, Mark H Ellisman, Alan Saghatelian
Upstream open reading frames (uORFs) are cis-acting elements that can dynamically regulate the translation of downstream ORFs by suppressing downstream translation under basal conditions and, in some cases, increasing translation under stress conditions. Computational and empirical methods have identified uORFs in the 5'-UTRs of approximately half of all mouse and human transcripts, making uORFs one the largest regulatory elements known. Because the prevailing dogma was that eukaryotic mRNAs produce a single functional protein, the peptides and small proteins, or microproteins, encoded by uORFs are under studied...
April 3, 2024: Journal of Molecular Biology
Hannah E Augustijn, Dimitris Karapliafis, Kristy M M Joosten, Sébastien Rigali, Gilles P van Wezel, Marnix H Medema
Actinobacteria undergo a complex multicellular life cycle and produce a wide range of specialized metabolites, including the majority of the antibiotics. These biological processes are controlled by intricate regulatory pathways, and to better understand how they are controlled we need to augment our insights into the transcription factor binding sites. Here, we present LogoMotif (, an open-source database for characterized and predicted transcription factor binding sites in Actinobacteria, along with their cognate position weight matrices and hidden Markov models...
April 3, 2024: Journal of Molecular Biology
Supreet Bhattacharya, Ankit Agarwal, Kalappa Muniyappa
The class II CRISPR-Cas9 and CRISPR-Cas12a systems, originally described as adaptive immune systems of bacteria and archaea, have emerged as versatile tools for genome-editing, with applications in biotechnology and medicine. However, significantly less is known about their substrate specificity, but such knowledge may provide instructive insights into their off-target cleavage and previously unrecognized mechanism of action. Here, we document that the Acidaminococcus sp. Cas12a (AsCas12a) binds preferentially, and independently of crRNA, to a suite of branched DNA structures, such as the Holliday junction (HJ), replication fork and D-loops, compared with single- or double-stranded DNA, and promotes their degradation...
April 2, 2024: Journal of Molecular Biology
Paola Pietrangeli, Lucia Marcocci, Valeria Pennacchietti, Awa Diop, Mariana Di Felice, Livia Pagano, Francesca Malagrinò, Angelo Toto, Maurizio Brunori, Stefano Gianni
The funneled energy landscape theory suggests that the folding pathway of homologous proteins should converge at the late stages of folding. In this respect, proteins displaying a broad energy landscape for folding are particularly instructive, allowing inferring both the early, intermediate and late stages of folding. In this paper we explore the folding mechanisms of human frataxin, an essential mitochondrial protein linked to the neurodegenerative disorder Friedreich's ataxia. Building upon previous studies on the yeast homologue, the folding pathway of human frataxin is thoroughly examined, revealing a mechanism implying the presence of a broad energy barrier, reminiscent of the yeast counterpart...
March 27, 2024: Journal of Molecular Biology
Marcell Szikszai, Marcin Magnus, Siddhant Sanghi, Sachin Kadyan, Nazim Bouatta, Elena Rivas
With advances in protein structure prediction thanks to deep learning models like AlphaFold, RNA structure prediction has recently received increased attention from deep learning researchers. RNAs introduce substantial challenges due to the sparser availability and lower structural diversity of the experimentally resolved RNA structures in comparison to protein structures. These challenges are often poorly addressed by the existing literature, many of which report inflated performance due to using training and testing sets with significant structural overlap...
March 27, 2024: Journal of Molecular Biology
Vaishali P Waman, Nicola Bordin, Rachel Alcraft, Robert Vickerstaff, Clemens Rauer, Qian Chan, Ian Sillitoe, Hazuki Yamamori, Christine Orengo
CATH ( classifies domain structures from experimental protein structures in the PDB and predicted structures in the AlphaFold Database (AFDB). To cope with the scale of the predicted data a new NextFlow workflow (CATH-AlphaFlow), has been developed to classify high-quality domains into CATH superfamilies and identify novel fold groups and superfamilies. CATH-AlphaFlow uses a novel state-of-the-art structure-based domain boundary prediction method (ChainSaw) for identifying domains in multi-domain proteins...
March 26, 2024: Journal of Molecular Biology
Sergey L Sedinkin, Julien Roche, Vincenzo Venditti
The catalytic cycle of Enzyme I (EI), a phosphotransferase enzyme responsible for converting phosphoenolpyruvate (PEP) into pyruvate, is characterized by a series of local and global conformational rearrangements. This multistep process includes a monomer-to-dimer transition, followed by an open-to-closed rearrangement of the dimeric complex upon PEP binding. In the present study, we investigate the thermodynamics of EI dimerization using a range of high-pressure solution NMR techniques complemented by SAXS experiments...
March 26, 2024: Journal of Molecular Biology
Abhinav Mittal, Douglas H Turner, David H Mathews
Nearest neighbor thermodynamic parameters are widely used for RNA and DNA secondary structure prediction and to model thermodynamic ensembles of secondary structures. The Nearest Neighbor Database (NNDB) is a freely available web resource ( that provides the functional forms, parameter values, and example calculations. The NNDB provides the 1999 and 2004 set of RNA folding nearest neighbor parameters. We expanded the database to include a set of DNA parameters and a set of RNA parameters that includes m6 A in addition to the canonical RNA nucleobases...
March 22, 2024: Journal of Molecular Biology
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